PROJECT SUMMARY/ABSTRACT Multiple myeloma (MM) is a life-threatening plasma cell malignancy. It is 2-3 times more common in blacks compared with whites. MM has a prolonged clinically detectable premalignant phase called monoclonal gammopathy of undetermined significance (MGUS) that can be identified by detection of the secreted monoclonal immunoglobulin (commonly referred to as a monoclonal protein). MM is a serious incurable malignancy, and the best approach for treatment is to prevent end organ damage by early intervention. This is best done by targeting patients with an intermediate asymptomatic stage referred to as smoldering multiple myeloma (SMM) that resides between MGUS and MM. Over the last 5 years of this grant we have extensively investigated the reasons why MM is more common in blacks compared with whites, demonstrated that first- degree relatives of patients with MM have a high risk of having the precursor MGUS lesion, and identified several biomarkers that predict risk of imminent progression in SMM. Our studies show that a principal reason for high risk of MM in African Americans is that they have a high risk of the precursor MGUS condition, which we also found is present at a much earlier in age in blacks compared with whites. More recently we made an important discovery using DNA sequencing based ancestry analysis that 3 specific cytogenetic abnormalities in MM account for most of the racial disparity. Our research has assumed greater urgency with recent findings that early intervention (in high-risk SMM stage) can prevent end-organ damage and prolong overall survival. The goals of this renewal are to further determine the mechanisms behind the racial disparity in incidence of MM, to identify new biomarkers for high risk SMM needing therapy, and to develop a feasible screening strategy to identify patients with SMM. In Aim 1 we will determine the age at onset of MGUS using sensitive, mass spectrometry (MS)-based detection of monoclonal protein in >12,000 NHANES samples, and identify new cytogenetic abnormalities that are associated with predisposition to MM in blacks. In Aim 2 we will identify new biomarkers that are associated with high risk of progression from SMM to symptomatic MM, specifically utilizing mass spectroscopic characterization of the monoclonal protein, measurement of circulating clonal plasma cells, and by studying clonal diversity and immune profile. In Aim 3, we will institute and determine the feasibility and impact of a screening approach for identification of SMM eligible for early intervention, by targeting high risk populations, specifically African Americans, first-degree relatives, and persons with high total protein levels. Our grant will have a major impact on the management of patients with SMM and MM, especially African Americans and first-degree relatives or persons with MM.